US8545820B2 - Use of titanium-based materials as bactericides - Google Patents
Use of titanium-based materials as bactericides Download PDFInfo
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- US8545820B2 US8545820B2 US13/135,745 US201113135745A US8545820B2 US 8545820 B2 US8545820 B2 US 8545820B2 US 201113135745 A US201113135745 A US 201113135745A US 8545820 B2 US8545820 B2 US 8545820B2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
- A61K8/29—Titanium; Compounds thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
Definitions
- This invention is directed towards the use of metal ions delivered from a solid phase material to suppress the growth of bacteria.
- APT amorphous peroxotitanate
- MST monosodium titanate
- a further aspect of at least one embodiment of the present invention is to provide a sustained-release oral ointment or paste which comprises a carrier ointment, an adhesive substance, and an anti-microbial metal ion which is attached to APT or MST.
- a further aspect of at least one embodiment of the present invention is to provide for an oral ointment in the form of a medicine, an injectable fluid, toothpaste, oral gel, paste, a denture cream, or an oral rinse which can deliver to a periodontal pocket, or a carious lesion, a therapeutic amount of a metal ion complexed with either APT or MST.
- FIG. 1 are dose response curves setting forth the effect of MST loaded with various metals and the effect of the growth rate of the bacteria listed in Table 2.
- FIG. 2 are dose response curves setting forth the effect of APT compounds loaded with the various metals and the effect on the growth rate of bacteria listed in Table 2.
- MST and an APT are known in the art from the use of such materials for sorbents of radionuclides.
- Various types of synthesis routes and characterization of MST and APT can be found in reference to the following publications.
- American Chemical Society A Family of Peroxo-titanate Materials Tailored for Optimal Strontium and Actinide Sorption Chem. Mater., 2006, 18 (26), page 6425-6435, and which is incorporated herein by reference. Additional background information with respect to titanate materials may be found in reference to U.S. Pat. No. 7,494,640, which is incorporated herein by reference and U.S. patent application Ser. No. 11/638,843 filed Dec. 14, 2006, and which is incorporated herein by reference.
- the MST is available as an aqueous suspension at ph 11.7 having approximately 15 wt % solids from Optima Chemical Groups, Douglas, Ga.
- the pH of a stock MST suspension was adjusted to 7.4 using a reagent grade nitric acid (Fisher).
- a stock solution of MST of 3,000 mg/L was diluted in sterile distilled water to working concentration as set forth below.
- APT was produced by treating MST with a solution of hydrogen peroxide. Excess hydrogen peroxide was removed by filtration. The isolated solids were washed with ionized distilled water and the APT solids were then suspended in water and adjusted to pH 4 with dilute nitric acid. In preparation of the metal-loaded APT materials as set forth below, a stock suspension of the APT was adjusted with NaOH solution to a pH of 7.4 and the solids content adjusted to 2000 mg/L.
- concentrations of metals in the loading solutions were maximized (limited by solubility in PBS) to provide the greatest driving force to load metal onto the particles.
- the amount of metal compounds loaded onto the titanate was determined by measuring the difference in metal concentrations of the metal loading solutions before and after contact with the titanate solids. Metal ion concentrations in the solutions before and after contact with the solids were determined using inductively coupled plasma emission spectroscopy (ICP-ES) and inductively coupled plasma mass spectroscopy (ICP-MS) techniques. Metal loading was reported as the number of picomoles (picomol) of metal per ⁇ g of titanate. As used herein, the term “metal loading” is used to refer to any form of attachment of the metal to the respective titanate. Such forms of interaction may include sorption or some type of ligand interaction.
- ionic or covalent bonding can be used including the use of other chemical reagents that might bring about improved binding of the metal to the titanate.
- conjugation through the use of proteins bound to one or more of the metals and/or titanates may be used.
- Table 1 Set forth in Table 1 are the species of oral bacteria which were evaluated. These species are atiologic agents and periodontal disease, gingivitis, or caries that would lend themselves to treatment with a solid-phase metal titanate compound.
- Porphyromonas gingivalis (Pg) (American Type Culture Collection #33277) was cultured under anaerobic conditions (85% N 2 , 10% H 2 , 5% CO 2 ) at 37° C. in trypticase soy broth (BBL, Sparks Md.) supplemented with 1 g of yeast extract, 5 mg of hemin, and 1 mg of menadione per L.
- Fusobacterium nucleatum (Fn) (ATCC #43718) and Agregatibacter actinomycetemcomitans (Aa) (ATCC #25586) were cultured in Todd-Hewitt broth supplemented with 10 g of yeast extract/L at 37° C. under the same anaerobic conditions.
- Streptococcus mutans (Sm) (ATCC #700610) was cultured under aerobic conditions (100% room air) at 37° C. in trypticase soy broth.
- Prevotella intermedia (ATCC #25611) was cultured under anaerobic conditions in trypticase soy broth supplemented with 0.5% yeast extract, 0.05% cysteine, 0.5 mg/mL hemin, and 2 ⁇ g/mL menadione, and Actinomyces naeslundii (An) (ATCC #19039) was cultured in an oxygen-depleted, N 2 -free atmosphere at 37° C. in BBL Actinomyces broth. All bacteria were cultured from frozen stocks expanded from ATCC cultures; the absence of contamination was verified at each thaw via Gram stain. All bacteria were grown over 24 h to mid-log phase before inoculating experimental cultures.
- Control cultures for experiments included cultures of media alone (no titanates or bacteria), titanates in media (no bacteria), and bacteria alone (no titanates). Additional control for bacteriostatic effect included bacteria with erythromycin (100 ⁇ g/mL, no titanates), which is an effective antibiotic against many oral pathogens. All experiments were repeated in triplicate to assure reproducibility.
- Titanate Loading Loaded Loaded Metal Source Concentration Concentration Concentration Concentration Concentration Ion compound Supplier ⁇ M
- g metal/g APT g metal/g MST
- Au(III) HAuCl 4 •3H 2 O Sigma-Aldrich 13,251 0.0852 0.0789
- Pd(II) PdCl 2 Johnson Mathey 13,240 0.0539 0.0557 Inc.
- the initial and final mean and standard deviation OD readings were plotted as a function of concentration.
- Metal ions differed in their ability to suppress planktonic bacterial growth of the species in Table 1. For example, An growth ( FIG. 1 ) was not suppressed by Pt(IV) concentrations ⁇ 750 ⁇ M, was suppressed approximately 30% by Pd(II)>1000 ⁇ M, and was completely suppressed by Au(III)>10 ⁇ M. We could not measure the effects of Pt(II) alone because of limited aqueous solubility of the chloride salt (Table 2); maximum concentrations of the other metal ions were limited by the aqueous solubility of their salts as well.
- the bacteria in Table 1 were equally susceptible to the metal ions alone.
- Au(III) was the most potent, inhibiting growth of Aa, An, Fn, and Pg by at least 50% above 10-50 ⁇ M (Table 3).
- concentrations of Au(III) ⁇ 1500 ⁇ M had no observable effect on Pi, which demonstrated the specificity of these effects on bacterial species.
- MST and APT in their sodium forms did not inhibit growth of any of the bacterial species as shown in Table 1 and FIGS. 2 and 3 .
- Growth of the bacterial control cultures varied somewhat by species although approximately equal starting numbers were used (FIGS. 2 , 3 ); Pg was the slowest growing of the bacteria tested (Table 1).
- the OD values of bacteria alone at 24 h were sufficient (0.3 to 1.2) to detect any inhibition by the titanates.
- Controls for medium alone (Med) and bacterial with erythromycin (Bac-Em) behaved as expected (FIGS. 2 , 3 ).
- Controls with titanates (no bacteria) had ODs of 0.1-0.15; thus the OD of the titanates did not obscure growth in experiments measuring the effects of loaded or unloaded titanates on bacterial growth.
- OD among the different metal-titanate compounds and titanates alone did not vary, and the window of OD between maximal bacterial growth and the OD of the metal-titanate compounds ranged from 0.3 to 0.9, providing a sufficient signal range to see any growth inhibition caused by the metal-titanate compounds. Variation among replicates in these tests were generally 10-15%, but sometimes greater (e.g., APT-Fn, FIG. 2 ).
- the bacteria evaluated in the study are all associated with periodontal disease or dental caries. It is believed that use of the titanate-mediated biodelivery system allows for an effective treatment of periodontal disease or dental caries. For instance, periodontal pockets associated with diseased gums could have an effective amount of the titanate-metal ion delivered to the pocket. Suitable delivery mechanisms may involve direct injection of a solution or ointment containing the titanate/metal ion complex. Other delivery mechanisms used to treat periodontal disease or dental caries may also be employed including the incorporation of the titanate/metal ion complex into various pastes, creams, salves, oral rinses, and similar products.
- the direct contact mechanism therefore seems likely, even more so than with mammalian cells, where cellular ‘ingestion’ of the titanate particles is plausible.
- the direct contact inhibition hypothesis if true, suggests that the metal-titanate compounds could be used in solid-phase disinfection schemes.
- Pd(II) and Pt(IV) ions are more potent inhibitors of mammalian cells than bacteria.
- the TC50 concentrations for these ions against the bacteria in Table 1 were >750-1500 ⁇ M (Table 3), yet Pd(II) inhibits mammalian cells at 100-300 ⁇ M and Pt(IV) at 25 ⁇ M based on previous reports. This differential is not encouraging for metal ions for systemic treatment of bacterial infections in human tissues.
- the metal-titanate compounds inhibited bacterial growth (e.g., Pi and Pg) with far lower metal ion loads (2-13 ⁇ M; Table 3).
- the titanates may provide a favorable shift of the therapeutic index for these metal ions as antibacterials.
- Au(III) these factors were more favorable because the inhibitory concentration for bacteria (often 10-50 ⁇ M, Table 3) was below that for several types of mammalian cells (60-115 ⁇ M, Ref 10), and titanates inhibited bacteria at effective doses of 0.4-11 ⁇ M (Table 3).
- Pt(II) the solubility of the ion alone was so low that its toxicity could not even be tested, yet Pt(II)-APT was an effective inhibitor of Aa and Pg growth at doses of only 0.11 ⁇ M (Table 3). All of these data suggest a therapeutic advantage of the metal-titanate compounds as antibacterials.
- metal-titanates could be used as an adjunct treatment at the base of carious lesions, in residual canals post-endodontic therapy, or incorporated into restorative materials to limit recurrent caries at the margins of restorations. Titanates could be used in any poorly perfused area to inhibit bacterial growth where the solid-phase would be advantageous; one example would be in osteomyelitis. On the skin, titanates might be used in bandages to limit bacterial growth in wounds or ingress into wounds.
- the current results show that by themselves, sodium titanates (MST or APT) have no effect on planktonic growth of several oral bacterial species, but that inhibition of growth is possible when Au(III), Pd(II), Pt(II), or Pt(IV) are loaded onto the MST or APT. Furthermore, the current results support a facilitative role for the titanates in metal-mediated inhibition of bacterial growth in some cases.
- titanate-metal ion delivery system can be used with any number of site specific medical delivery systems so as to target a metal ion to a specific organ or region of the body.
- site specific medical delivery systems so as to target a metal ion to a specific organ or region of the body.
- various monoclonal or polyclonal antibodies could possibly be conjugated to the titanate-metal ion complex so as to deliver the complex to a targeted region.
- Other well known targeting systems including various ligands, lectins or chemical carriers may be utilized as well as various mechanical delivery systems for targeting delivery of a therapeutic region to a specified location or region.
- any metal ion having an ability to suppress bacterial growth may be utilized with the titanate delivery system described herein.
- the titanate delivery system has a beneficial synergistic effect with respect to the metal ion and the bacterium of interest such that the synergistic properties of the titanate-metal ion complex are achieved.
- metal-loaded titanates can be incorporated into traditional medical ointments, bandages, implantable biomaterials, coatings on invasive apparatuses such as catheters, shunts, and similar devices to prevent or limit bacterial infections.
- the metal-loaded titanates are believed to be compatible with traditional antibiotic ointments and creams.
- Metal-loaded titanate may also be incorporated as coatings on surgical suture material to help suppress growth and/or formation of bacterial infections.
Abstract
Description
TABLE 1 |
Bacteria evaluated |
Bacteria | Source | Gram | |||
(Code) | Full Name | (ATCC*) | Staining | Role in oral disease | Culture condition |
Aa | Aggregatibacter | 25586 | negative | aggressive periodontal | anaerobic (85%N2, |
actinomycetemcomitans | pathogen | 10%H2, 5% CO2) | |||
An | Actinomyces naeslundii | 19039 | positive | root caries, early childhood | N2-free, O2 depleted |
caries | |||||
Fn | Fusobacterium nucleatum | 43718 | negative | bridging organism between | anaerobic (85%N2, |
pathogens and non-pathogens | 10%H2, 5% CO2) | ||||
Pg | Porphyromonas gingivalis | 33277 | negative | periodontal pathogen | anaerobic (85%N2, |
10%H2, 5% CO2) | |||||
Pi | Prevotella intermedia | 25611 | negative | gingival and periodontal | anaerobic (85%N2. |
pathogen | 10%H2, 5% CO2) | ||||
*American Type Culture Collection number. |
Exposure of Bacteria to Metal Ions, Titanates, and Metal-Titanium Compounds
TABLE 2 |
Metal compounds and titanate loading. |
Titanate Loading | Loaded | Loaded | |||
Metal | Source | Concentration | Concentration | Concentration | |
Ion | compound | Supplier | (μM) | (g metal/g APT) | (g metal/g MST) |
Au(III) | HAuCl4•3H2O | Sigma-Aldrich | 13,251 | 0.0852 | 0.0789 |
Pd(II) | PdCl2 | Johnson Mathey, | 13,240 | 0.0539 | 0.0557 |
Inc. | |||||
Pt(II) | PtCl2 | Johnson Mathey, | 114 | 0.00086 | 0.00084 |
Inc. | |||||
Pt(IV) | PtCl2 | Johnson Mathey, | 14,912 | 0.0155 | 0.0686 |
Inc. | |||||
TABLE 3 |
Suppression of bacterial growth by metal ions and metal-titanate compounds. |
TC50 | MST-metal compound | APT-metal compound |
Conc., | Max. | Max. | Titanate | Max. | Max. | Titanate | ||||
Metal | Bacterial | Metal | Enhancement | Bacterial | Metal | Enhancement | ||||
ion | Growth | Inhibitory | ion | of Metal | Growth | Inhibitory | ion | of Metal | ||
Metal | Alone | Suppression | Conc. | Delivery | Suppression | Suppression | Conc. | Delivery | Suppression | |
Bacteria | Ion | (μM)* | (%) | (μg/mL)** | (μM)*** | (fold)**** | (%) | (μg/mL)** | (μM)*** | (fold)**** |
Aa | Au(III) | 10 | 100# | 5# | 2 | 5 | 10 | 25 | — | — |
Pd(II) | 1500 | 0 | — | — | — | 25 | 10 | — | — | |
Pt(II) | ND@ | 0 | — | — | — | 60# | 25# | 0.11 | — | |
Pt(IV) | >1500 | 20 | 25 | — | — | 30# | 25# | — | — | |
An | Au(III) | 50 | 80# | 20# | 8 | 6 | 0 | — | — | — |
Pd(II) | >1500 | 10 | 25 | — | — | 10# | 10# | — | — | |
Pt(II) | ND | 0 | — | — | — | 0 | — | — | — | |
Pt(IV) | >750 | 0 | — | — | — | 0 | — | — | — | |
Fn | Au(III) | 10 | 100# | 5# | 2 | 5 | 40 | 25 | — | — |
Pd(II) | 1000 | 0 | — | — | — | 30 | 10 | — | — | |
Pt(II) | ND | 0 | — | — | — | 25 | 25 | — | — | |
Pt(IV) | 750 | 0 | — | — | — | 35 | 10 | — | — | |
Pg | Au(III) | 10 | 100# | 1# | 0.4 | 25 | 100# | 25# | 11 | 0.9 |
Pd(II) | >1500 | 45# | 25# | — | — | 100# | 25# | 13 | >190 | |
Pt(II) | ND | 20 | 25 | — | — | 100# | 25# | — | — | |
Pt(IV) | >750 | 40# | 25# | — | — | 100# | 25# | 2 | >375 | |
Pi | Au(III) | >1500 | 30# | 25# | — | — | 30# | 25# | — | |
Pd(II) | 1500 | 60# | 25# | 13 | 115 | 15# | 25# | — | ||
Pt(II) | ND | 30# | 25# | — | — | 30# | 10# | — | ||
Pt(IV) | >750 | 60# | 10# | 3.5 | >210 | 60# | 25# | 2 | >375 | |
Red cells indicate that bacterial growth suppression was ≧50% vs. titanate controls. Green indicates that titanates enhanced metal interactions with bacteria. | ||||||||||
*Concentration that suppressed bacterial growth by ≧50% vs control | ||||||||||
**Concentration of loaded metal-titanate compound that suppressed bacterial growth maximally relative to titanate-only controls. | ||||||||||
***Assuming that all of the loaded metal was delivered to the bacteria from the inhibitory metal-titanate concentration. | ||||||||||
*****TC50 concentration of ion alone to divided by the maximal delivered concentration when titanate-compound suppressed bacterial growth by ≧50% vs. controls. | ||||||||||
#Statistical significance vs. titanate-only controls (paired t-test, α = 0.05). | ||||||||||
@Not done. Concentration of Pt(II) solution not high enough for cell-culture experiments at high Pt(II) concentrations. | ||||||||||
— Not calculated because conditions for accurate calculations not met or data not available. |
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4229430A (en) * | 1978-08-21 | 1980-10-21 | Fahim Mostafa S | Oral composition for improving oral health |
US5688492A (en) * | 1992-05-22 | 1997-11-18 | The Boots Company Plc, | Oral hygiene composition |
US20080145450A1 (en) | 2006-12-14 | 2008-06-19 | Hobbs David T | Delivery or removal of metals from biological systems |
US20080142448A1 (en) | 2006-12-14 | 2008-06-19 | Hobbs David T | Treatment of metal-containing liquids |
US7494640B1 (en) | 2005-06-29 | 2009-02-24 | Sandia Corporaion | Hydrogen peroxide modified sodium titanates with improved sorption capabilities |
-
2011
- 2011-07-14 US US13/135,745 patent/US8545820B2/en active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4229430A (en) * | 1978-08-21 | 1980-10-21 | Fahim Mostafa S | Oral composition for improving oral health |
US5688492A (en) * | 1992-05-22 | 1997-11-18 | The Boots Company Plc, | Oral hygiene composition |
US7494640B1 (en) | 2005-06-29 | 2009-02-24 | Sandia Corporaion | Hydrogen peroxide modified sodium titanates with improved sorption capabilities |
US20080145450A1 (en) | 2006-12-14 | 2008-06-19 | Hobbs David T | Delivery or removal of metals from biological systems |
US20080142448A1 (en) | 2006-12-14 | 2008-06-19 | Hobbs David T | Treatment of metal-containing liquids |
Non-Patent Citations (3)
Title |
---|
American Chemical Society, Nyman and Hobbs "A Family of Peroxo-Titanate Materials Tailored for Optimal Strontium and Actinide Sorption" Chem. Matter, Published on Web Nov. 18, 2006, 18 (26), p. 6425-6435 (11Pages). |
Hobbs et al., "Absorption of Biometals to Monosodium Titanate in Biological Environments", Journal of Biomedical Materials Research Part B: Applied Biomaterials, vol. 78B, Issue 2, pp. 296-301, Aug. 2006. * |
The Journal of Biomedical Materials Reasearch, Chung et al.; "Peroxotitanate-and Monosodium Metal-Type Tinate Compound As Inhibitors of Bacterial Growth", Jun. 2011 vol. 97A, Issue 3, pp. 348-354. |
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